Effect of oral health on efficacy of immune checkpoint inhibitors

• Project/Area Number: 19K19332
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57080:Social dentistry-related
• Research Institution: Nara Medical University
• Principal Investigator: Nakashima Chie 奈良県立医科大学, 医学部, 研究員 (40812657)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 細菌叢 / ウェルシュ菌 / クローディン4 / YAP / 上皮間葉移行 / がん幹細胞性 / 非タイトジャンクションクローディン4 / がん悪性化 / EMT / Clostridium / Claudin4 / SSA/P / CPE / 口腔扁平上皮癌 / 口腔内細菌 / Clostridium perfringens / 口腔衛生 / 口腔細菌叢 / 自然免疫 / 免疫チェックポイント

Outline of Research at the Start

「口腔内衛生環境の改善が全身の抗腫瘍免疫の改善に役立つのか」と言う問いに解答を出そうとするものであり、①口腔内衛生環境と全身自然免疫系チェックポイントとの関連を明らかにし、②口腔内衛生環境の癌の進展への影響を免疫系との関連性から解明する。③さらに、口腔内衛生環境が獲得免疫系チェックポイント阻害剤の効果に影響を与えることを明らかにし、④最終的には、殺菌作用を有する含嗽剤の使用による口腔衛生の保持が、自然免疫系チェックポイント・獲得免疫系チェックポイントの両者の制御に有用であることを示すことを目的とする。

Outline of Final Research Achievements

Although C. perfringens impair tight junctions, in oral squamous cell carcinoma, intratumoral C. perfringens induced YAP activation through intracellular translocation of claudin-4, resulting in enhanced EMT and stemness. Similarly, C. perfringens was found to contribute to the malignant transformation of colon cancer precancerous lesions SSA/P-D. Furthermore, in renal cell carcinoma, EphA2-PKCε resulted in the activation of YAP by intracellular translocation of claudin-4, similar to C. perfringens. Thus, the non-tight junction claudin-4-YAP pathway may represent a novel target for cancer therapy.

Academic Significance and Societal Importance of the Research Achievements

体内細菌叢の細菌と癌との関係は未だ不明な点が多い。この腫瘍－細菌連関の免疫や発癌への影響をタイトジャンクションという切り口から解明することにより、新たな癌の悪性化機序を見出し、新規治療標的を抽出することを本研究の目的とする。本研究の結果は、腫瘍－細菌連関を標的とする口腔衛生、プロバイオティックスや分子標的治療の開発に有用な知見をもたらすことが期待される。

Research Products

• [Int'l Joint Research] Nantong university(中国)
• [Int'l Joint Research] 南通大学(中国)
• [Int'l Joint Research] 南通大学(中国)
• [Journal Article] Suppressive GLI2 fragment enhances liver metastasis in colorectal cancer (2022)
  • Author(s): Ogata Ruiko、Mori Shiori、Ohmori Hitoshi、Kishi Shingo、Fujiwara-Tani Rina、Sasaki Takamitsu、Nishiguchi Yukiko、Nakashima Chie、Goto Kei、Kawahara Isao、Luo Yi、Kuniyasu Hiroki
  • Journal Title: Oncotarget Volume: 13 Issue: 1 Pages: 122-135
  • DOI: 10.18632/oncotarget.28170
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sunitinib and Pterostilbene Combination Treatment Exerts Antitumor Effects in Gastric Cancer via Suppression of PDZD8 (2022)
  • Author(s): Hojo Yudai、Kishi Shingo、Mori Shiori、Fujiwara-Tani Rina、Sasaki Takamitsu、Fujii Kiyomu、Nishiguchi Yukiko、Nakashima Chie、Luo Yi、Shinohara Hisashi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 7 Pages: 4002-4002
  • DOI: 10.3390/ijms23074002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Axis between the Long Non-Coding RNA HOXA11-AS and NQOs Enhances Metastatic Ability in Oral Squamous Cell Carcinoma (2022)
  • Author(s): Nakashima Chie、Fujiwara-Tani Rina、Mori Shiori、Kishi Shingo、Ohmori Hitoshi、Fujii Kiyomu、Mori Takuya、Miyagawa Yoshihiro、Yamamoto Kazuhiko、Kirita Tadaaki、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 18 Pages: 10704-10704
  • DOI: 10.3390/ijms231810704
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Glycated High Mobility Group Box-1 in Gastric Cancer (2021)
  • Author(s): Kishi Shingo、Nishiguchi Yukiko、Honoki Kanya、Mori Shiori、Fujiwara-Tani Rina、Sasaki Takamitsu、Fujii Kiyomu、Kawahara Isao、Goto Kei、Nakashima Chie、Kido Akira、Tanaka Yasuhito、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 10 Pages: 5185-5185
  • DOI: 10.3390/ijms22105185
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer (2021)
  • Author(s): Mori Shiori、Fujiwara-Tani Rina、Kishi Shingo、Sasaki Takamitsu、Ohmori Hitoshi、Goto Kei、Nakashima Chie、Nishiguchi Yukiko、Kawahara Isao、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 15 Pages: 8232-8232
  • DOI: 10.3390/ijms22158232
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer (2021)
  • Author(s): Fujiwara-Tani Rina、Okamoto Ayaka、Katsuragawa Hiroyuki、Ohmori Hitoshi、Fujii Kiyomu、Mori Shiori、Kishi Shingo、Sasaki Takamitsu、Nakashima Chie、Kawahara Isao、Hojo Yudai、Nishiguchi Yukiko、Mori Takuya、Mizumoto Takeshi、Nagai Kenta、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 23 Pages: 12724-12724
  • DOI: 10.3390/ijms222312724
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clostridium perfringens enterotoxin induced claudin-4 to activate YAP in oral squamous cell carcinomas. (2020)
  • Author(s): Nakashima C, Yamamoto K, Kishi S, Sasaki T, Ohmori H, Fujiwara-Tani R Mori S, Kawahara I, Nishiguchi Y, Mori T, Kondoh M, Luo Y, Kirita T, Kuniyasu H
  • Journal Title: Oncotarget Volume: 11 Issue: 4 Pages: 309-321
  • DOI: 10.18632/oncotarget.27424
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Malic enzyme 1 is associated with tumor budding in oral squamous cell carcinomas. (2020)
  • Author(s): Nakashima C, Kirita T, Yamamoto K, Mori S, Luo Y, Sasaki T, Fujii K, Ohmori H, Kawahara I, Mori T, Goto K, Kishi S, Fujiwara-Tani R, Kuniyasu H
  • Journal Title: Int J Mol Sci Volume: 21 Issue: 19 Pages: 7149-7149
  • DOI: 10.3390/ijms21197149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Proton Pump Inhibitors on Colorectal Cancer (2020)
  • Author(s): Sasaki Takamitsu、Mori Shiori、Kishi Shingo、Fujiwara-Tani Rina、Ohmori Hitoshi、Nishiguchi Yukiko、Hojo Yudai、Kawahara Isao、Nakashima Chie、Fujii Kiyomu、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 11 Pages: 3877-3877
  • DOI: 10.3390/ijms21113877
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of cancer-derived myocardial impairments using a mouse model (2020)
  • Author(s): Miyagawa Yoshihiro、Nukaga Shota、Mori Takuya、Fujiwara-Tani Rina、Fujii Kiyomu、Mori Shiori、Goto Kei、Kishi Shingo、Sasaki Takamitsu、Nakashima Chie、Ohmori Hitoshi、Kawahara Isao、Luo Yi、Kuniyasu Hiroki
  • Journal Title: Oncotarget Volume: 11 Issue: 41 Pages: 3712-3722
  • DOI: 10.18632/oncotarget.27759
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/Polyps with Dysplasia (2020)
  • Author(s): Fujiwara-Tani Rina、Fujii Kiyomu、Mori Shiori、Kishi Shingo、Sasaki Takamitsu、Ohmori Hitoshi、Nakashima Chie、Kawahara Isao、Nishiguchi Yukiko、Mori Takuya、Sho Masayuki、Kondoh Masuo、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 11 Pages: 3840-3840
  • DOI: 10.3390/ijms21113840
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Concurrent Expression of CD47 and CD44 in Colorectal Cancer Promotes Malignancy (2019)
  • Author(s): Fujiwara-Tani Rina、Sasaki Takamitsu、Ohmori Hitoshi、Luo Yi、Goto Kei、Nishiguchi Yukiko、Mori Shiori、Nakashima Chie、Mori Takuya、Miyagawa Yoshihiro、Kawahara Isao、Fujii Kiyomu、Kishi Shingo、Tatsumoto Naokuni、Kuniyasu Hiroki
  • Journal Title: Pathobiology Volume: 86 Issue: 4 Pages: 182-189
  • DOI: 10.1159/000496027
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 口腔扁平上皮癌におけるHXA11-AS-NQO1/NQO2 axisの役割 (2023)
  • Author(s): 中嶋千恵、谷里奈、森汐莉、岸真五、山本一彦、桐田忠昭、國安弘基
  • Organizer: 第112回日本病理学会総会、下関市、2023.4.13-15
• [Presentation] Malic enzyme 1 は口腔扁平上皮癌における腫瘍のbuddingと関連する (2022)
  • Author(s): 中嶋千恵、谷里奈、岸真五、森汐莉、山本一彦、桐田忠昭、國安弘基
  • Organizer: 第111回日本病理学会総会、神戸市（ハイブリッド開催）、2022.4.14-16
• [Presentation] CPEはOSCCにおいてYAPとCLDN4の核内移行を誘発する (2022)
  • Author(s): 中嶋千恵、谷里奈、岸真五、森汐莉、山本一彦、桐田忠昭、國安弘基
  • Organizer: 第46回日本頭頚部癌学会、奈良市、2022.6.17-18
• [Presentation] Malic enzyme 1 is associated with tumor budding in oral squamous cell carcinomas. (2022)
  • Author(s): Nakashima C, Fujiwara-Tani R, Kishi S, Mori S, Yamamoto K, Kirita T, Kuniyasu H
  • Organizer: 81th Annual Meeting of Japanese Association for Cancer, Yokohama, 2022.9.29-10.1
• [Presentation] Clostridium perfringens enterotoxin activates YAP in oral squamous cell carcinomas (2020)
  • Author(s): Nakashima C, Yamamoto K, Kishi S, Sasaki T, Ohmori H, Fujiwara-Tani R, Mori S, Fujii K, Nishiguchi Y, Kondoh M, Tadaaki K, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] 5-aminolevulinic acid enhance radiosensitivity thorough mitochondria reactive oxygen species burst in prostate cancer (2019)
  • Author(s): Owari T, Miyake M, Kishi S, Fujiwara-Tani R, Mori S, Mori T, Nakashima C, Nakai Y, Fujimoto K, Kuniyasu H
  • Organizer: 78th Annual Meeting of Japanese Association for Cancer
• [Remarks] 奈良県立医科大学分子病理学講座
  • URL: http://www.naramed-u.ac.jp/~molepath/
• [Remarks] 奈良県立医科大学分子病理学
  • URL: http://www.naramed-u.ac.jp/~molepath/